Dysbindin-1 is encoded by the dystrobrevin-binding protein-1 gene and is located in pre- and postsynaptic sites throughout human and mouse brain. Genetic variations in DTNBP1 affect human cognition and have been associated with risk for schizophrenia. Reduced dysbindin gene and protein expression have been seen in the prefrontal cortex and hippocampus of schizophrenia patients and suggests a molecular phenotype associated with schizophrenia which is reduced expression of dysbindin. Mutant mice with diminished DTNBP1 expression have become an informative animal model of reduced dysbindin protein. The role of dysbindin in dopamine (DA) and glutamate signaling, which are neurotransmitters at the center of neurochemical hypothesis of psychosis, is generally accepted. A pathogenic role of dysbindin is as a partner in the biogenesis of lysosome-related organelle, complex BLOC-1. Dysbindin is involved in intracellular protein trafficking using lysosomes and related organelles and is important for synaptic homeostasis. Many receptors including D2 and NR2A subunits are trafficked after internalization by lysosome-mediated degradation and dysbindin has been shown to affect these trafficking events. Disrupted dysbindin mice show alterations in internal trafficking of these specific components of DA and glutamine signaling and not other receptors that are not trafficked through the lysosome degradation pathway. We suggests that dysbindin reductions may represent a direct genetic bridge between the DA and glutamine schizophrenia-related signaling systems concluding that the molecular mechanism of DTNBP1 as a psychosis risk gene may involve this bridge. Future research will follow dysbindin in a search for ways to individualize treatment outcomes using both current and future therapeutic compounds. In a follow-up study of dysbindin, we investigated dysbindin-1 regulated D2 trafficking and examined whether it has implications in schizophrenia and related cognitive and behavioral abnormalities. It remains unknown whether the effects of dysbindin-1 regulated D2 trafficking mediates clinical manifestations of the disorder. Using dysbindin-1 null (-/-) and deficit (+/-) mice, which have reduced dysbindin protein expression, we examined schizophrenia-related behaviors;molecular and electrophysiological changes in pyramidal neuronal excitability in medial prefrontal cortex layers II/III;expression of calcium/calmodulin-dependent protein kinase family (CaMK) for their role in learning, memory, and DA trafficking;and dependence of events on D2-receptor stimulation. DA signaling is critical for modulating higher order cognitive functions, which impact human behavior, thought and emotion. The null mutant mouse line, derived from the native sandy mice strain, which have abnormal behavioral phenotypes referable to the DA system, were transferred onto B6 mice and backcrossed 11 generations to remove the effects on behavior and DA function. In addition, null and reduced dysbindin mutated mice were also shown to have reduced CaMKII and CaMKK(beta). We observed that disruption in the dysbindin gene affected working memory, stress responses, intracortical pyramidal cell excitability and medial prefrontal cortex CaMK subunits. In addition we demonstrated that mutated dysbindin affects sensitivity to D2 agonists and antagonists. The mutated dysbindin mouse strain had similar behavioral and molecular effects that were produced by direct pharmacological challenges to the DA/D2 pathways in the +/+ mice. Our findings demonstrated that dysbindin -/- mice on B6 background can be used as a model of dysbindin deficiencies. We showed the impact of DA/D2 pathways on functions such as working memory (improved acquisition and decreased performance);increased sensitivity to startle and stress tests;and decreased firing rate of neuronal excitability in layers II/III, which could underlie a molecular mechanism for the association of dysbindin with psychosis and cognitive dysfunction. Additionally, we discovered that dysbindin does play a role in CaMK regulation in the medial prefrontal cortex. DA/D2-like receptors impact the regulation of CaMK subunits, CaMKII and CaMKK(beta). Dysbindin mutant mice have reduced levels of CaMKII and CaMKK(beta). Chronic treatment with D2 agonist in dysbindin +/+mice produced similar decreases in CaMKII and CaMKK(beta) levels, indicating that these molecular changes in dysbindin -/- mutant mice are dependent in part on their increased D2 signaling. It has been reported that drug induced D2 stimulation increases intracellular calcium, which activates CaMKII and decreases the CaM-dependent phosphorylation of striatal membranes. Taken together, our findings show that genetically altered dysbindin can impact cognition through an effect on DA/D2 mechanisms in the mouse dorsal lateral prefrontal cortex giving insight into how reductions in dysbindin can promote cognitive deficits and psychosis in schizophrenia. Cognitive dysfunction is a core feature of schizophrenia and precedes the manifestation of psychosis. Genetic mouse models have contributed critical information about brain mechanisms involved in cognitive processes. Current treatments do not effectively improve cognitive symptoms. Since cognitive symptoms can be effectively modeled in mice these systems can be used to identify potential novel treatments for schizophrenia. Animal models may also help us to understand how single gene mutations might impact distinct cognitive functions, gene-gene and gene-environment interactions implicated in the cognitive abnormalities in schizophrenia. However, there are caveats to consider when using these models: there are many inconsistencies, missing tests, method confounds and difficulties in interpretation as evidenced in the current body of literature. Given these precautions, our group will continue to look at animal models to inform about brain mechanisms involved in cognitive processes as discussed in the aforementioned investigations. For example genes linked to schizophrenia based on functional hypotheses and some by genetic association (i.e. DA, glutamate, GABA, acetylcholine, and calcium), when used in genetically modified mouse models may allow us to better characterize cognitive processes and dysfunction. We will also use mouse models to interrogate risk-associated genes for schizophrenia (i.e. dysbindin, neuregulin, disrupted in schizophrenia 1, reelin, proline dehydrogenase) which were derived primarily from clinical genetic studies and lastly, corticotropin-releasing factor, brain-derived neurotrophic factor and endocannabinoid systems are reported environmental factors that impact stress-sensitive systems thought to contribute to the development of schizophrenia. Genetically modified mouse models for genes relevant to schizophrenia continue to hold great promise and offer unique advantages in understanding the function of genes and their contribution to the pathophysiology of cognitive schizophrenia-related abnormalities. Our approach allows for the detailed analysis of molecular and cellular pathways, the neural circuits and behaviors affected, early mutational effects and their developmental progression. Genetic mutations in clinically relevant neurotransmission signaling systems altered in schizophrenia may implicate pathophysiologic molecular networks, but it must be noted that these events may not reflect the primary disease causation, but rather related phenomena. Conversely, mutations in schizophrenia-susceptibility genes mimicking human risk alleles might address potential primary causes of the disease however genetic effects in mice do not directly link to clinical biology in humans. Combining these two approaches might be necessary to better understand the genetic pathways implicated in these specific cognitive deficits.